Acyl dihydropyrazolo[1,5-a]pyrimidinones as metabotropic glutamate receptor 5 positive allosteric modulators

详细信息    查看全文

• 作者：Chrysa Malosh^a ; ^b ; ^c ; ^d ; Mark Turlington^a ; ^b ; ^c ; ^d ; Thomas M. Bridges^a ; ^b ; ^c ; Jerri M. Rook^a ; ^b ; ^c ; Meredith J. Noetzel^a ; ^b ; ^c ; Paige N. Vinson^a ; ^b ; ^c ; Thomas Steckler^e ; Hilde Lavreysen^e ; Claire Mackie^f ; Jos&eacute ; M. Bartolom&eacute ; -Nebreda^g ; Susana Conde-Ceide^g ; Carlos M. Martí ; nez-Viturro^g ; Marí ; a Piedrafita^g ; M. Rosa Sá ; nchez-Casado^g ; Gregor J. Macdonald^e ; J. Scott Daniels^a ; ^b ; ^c ; Carrie K. Jones^a ; ^b ; ^c ; Colleen M. Niswender^a ; ^b ; ^c ; P. Jeffrey Conn^a ; ^b ; ^c ; Craig W. Lindsley^a ; ^b ; ^c ; ^d ; Shaun R. Stauffer^a ; ^b ; ^c ; ^d ; ^{shaun.stauffer@vanderbilt.edu" class="auth_mail" title="E-mail the corresponding author}
• 关键词：Metabotropic glutamate receptor 5 (mGlu5) ; Positive allosteric modulator (PAM)
• 刊名：Bioorganic & Medicinal Chemistry Letters
• 出版年：2015
• 出版时间：15 November 2015
• 年：2015
• 卷：25
• 期：22
• 页码：5115-5120
• 全文大小：3480 K

文摘

We report the optimization of a series of metabotropic glutamate receptor 5 (mGlu₅) positive allosteric modulators (PAMs) from an acyl dihydropyrazolo[1,5-a]pyrimidinone class. Investigation of exocyclic amide transpositions with this unique 5,6-bicyclic core were conducted in attempt to modulate physicochemical properties and identify a suitable backup candidate with a reduced half-life. A potent and selective PAM, 1-(2-(phenoxymethyl)-6,7-dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl)ethanone (9a, VU0462807), was identified with superior solubility and efficacy in the acute amphetamine-induced hyperlocomotion (AHL) rat model with a minimum effective dose of 3 mg/kg. Attempts to mitigate oxidative metabolism of the western phenoxy of 9a through extensive modification and profiling are described.